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EphrinB ligands and their Eph receptor tyrosine kinases are known to regulate excitatory synaptic functions in the hippocampus. In the CA3-CA1 synapse, ephrinB ligands are localized to the post-synaptic membrane, while their cognate Eph receptors can be expressed in both pre-and post-synaptic membranes. Previous studies show that interaction of ephrinB molecules with Eph receptors leads to changes in long-term potentiation (LTP), suggesting that reverse signaling through postsynaptic ephrinBs may be required for learning and memory. Our collaborative studies demonstrate that the cytoplasmic domain of ephrinB3, and hence reverse signaling, is not required for ephrinB-dependent learning and memory tasks or for LTP of these synapses. We demonstrate that ephrinB3 null mutants show changes in several synaptic proteins including reduced levels of NMDA receptor subunits. These abnormalities are not observed in ephrinB3lacZ reverse signaling mutants, supporting an Eph receptor forward signaling role for ephrinB3 in these processes. NMDA receptors are important in regulating synaptic functions and plasticity in the adult hippocampus, and Eph receptors have been shown to cluster NMDA receptors to the cell membrane. These studies show that ephrinB3 interacts with EphA4 to regulate plasma membrane levels of NR1 in Cos-1 cells and primary hippocampal neurons. In the absence of ephrinB3, NR1 levels are decreased in synaptosomal membranes, increased in microsomal tissues, but not changed in total extracts. This suggests that ephrinB3 regulates NR1 levels through protein trafficking and not gene transcription. Analysis of protein trafficking confirmed that ephrinB3 specifically interacts with EphA4 receptor to regulate NR1 exocytosis but not endocytosis in both transfected Cos-1 cells and primary hippocampal neurons. We postulate that ephrin-Eph receptor interactions are important mediators of synaptic formation and function, in part, through their regulation of NMDA receptors in the hippocampal synapse. In addition, we find that both ephrinB3KO and ephrinB3lacZ mice show an increased number of excitatory synapses, demonstrating a cytoplasmic-dependent reverse signaling role of ephrinB3 in regulating synapse number. Together, these data suggest that ephrinB3 may act like a receptor to transduce reverse signals to regulate the number of synapses formed in the hippocampus, and that it likely acts to stimulate forward signaling through Eph receptors to modulate NMDA receptor trafficking, LTP and learning.
Plasticity; Glutamate Receptors; Ephrins; Eph Receptors
Rodenas-Ruano, Alma Ileana, "EphrinB3 and Eph Receptors Regulate Hippocampal Synaptic Function" (2008). Open Access Dissertations. 34.